An important and prototypical type of pulmonary fibrosis occurs after exposure to asbestos, which results in an interstitial pneumonitis and subsequent collagen deposition. Although strict regulatory controls are in place to limit exposure, more than 1.3 million workers continue to be exposed to hazardous levels of asbestos annually (Attfield, M. D., et al., (Reprinted from MMWR, vol 53, pg 627-632, 2004), Jama-Journal of the American Medical Association 2004, 292, 795-796; and Guidotti, T. L., et al., American Journal of Respiratory and Critical Care Medicine 2004, 170, 691-715).
The development of pulmonary fibrosis is a complex process that results in aberrant remodeling of lung tissue. The modulation of lung remodeling during pulmonary fibrosis is poorly understood, and no effective therapeutic options have come about to prevent disease development. Thus, understanding the mechanism(s) by which aberrant remodeling is regulated may provide a potential target for therapy.
The generation of reactive oxygen species (ROS), including H2O2, plays a critical role in tissue injury and consequent fibrosis by modulating extracellular matrix deposition (Murthy, S., et al., J. Biol. Chem. 2010, 285, 25062-25073; and He, C., et al., J. Biol. Chem. 2011, 286, 15597-15607). The production of ROS is accentuated by the inefficient phagocytosis of asbestos fibers by alveolar macrophages (Mossman, B. T., et al., Environmental Health Perspectives 1989, 81, 91-94). It has been shown that alveolar macrophages obtained from patients with pulmonary fibrosis produce high levels of H2O2 and that the primary source of H2O2 generated in alveolar macrophages in the setting of pulmonary fibrosis is the mitochondria (He, C., et al., J. Biol. Chem. 2011, 286, 15597-15607). The generation of H2O2 is critical for the fibrotic response in lung injury because abrogating mitochondrial oxidant stress or administration of catalase attenuates the development of pulmonary fibrosis in mice (He, C., et al., J. Biol. Chem. 2011, 286, 15597-15607; and Murthy, S., et al., American Journal of Physiology-Lung Cellular and Molecular Physiology 2009, 297, L846-L855. Rac1 is a member of the Rho family of guanosine 5′-triphosphate (GTP)-binding proteins. Rac1 regulates several cellular functions, such as actin polymerization and migration, cell adhesion, and phagocytosis in macrophages, which are all necessary processes to engulf asbestos fibers (Hall, A. B., et al., Immunity 2006, 24, 305-316; Roberts, A. W., et al., Immunity 1999, 10, 183-196; and Wells, C. M., et al., J. Cell Sci. 2004, 117, 1259-1268). The C-terminal cysteine residue in Rho GTP-binding proteins, such as Rac1, can be modified by geranylgeranylation. This post-translational modification is important for Rac1 activation and interaction with other proteins (Zeng, P. Y., et al., Oncogene 2003, 22, 1124-1134).
It has recently been demonstrated that Rac1 is active in the alveolar macrophages of obtained from patients with asbestosis (Osborn-Heaford, H. L., et al., J. Biol. Chem. 2012, 287, 3301-3312.). This report also demonstrated that the Rac1 activation in the mitochondria of alveolar macrophages increases reactive oxygen species (ROS) such as peroxide in the lung, and that mice null for Rac1 show less ROS and decreased fibrosis relative to wild-type mice. The activity of Rac1 in this regard was shown to be dependent on the C-terminal cysteine residue of Rac1. U.S. Pat. No. 7,268,124 and International Application WO2014/008407 describe compounds that are reported to have activity as GGPP Synthase inhibitors.
There is currently a need for compounds and methods that are useful for treating fibrosis such as pulmonary fibrosis.